1. Field of the Invention
The present invention relates to amide derivatives which have superior anti-inflammatory and analgesic activities, and pharmaceutical compositions which comprise such an amide derivative as an active ingredient. The present invention further relates to methods of using such an amide derivative and such a pharmaceutical composition.
2. Discussion of the Background
It is considered that pain is developed by direct stimuli from damage and invasion of tissue based on various exogenous factors, amplified by various endogenous algetic substances produced by tissue damage and results in inflammatory conditions (Tanaka et al. ed.: NEW Yakurigaku, Nankodo Co., Ltd., Apr. 15, 2002, pp. 354-355). In addition, there is a pain caused by a functional abnormality of the peripheral nervous system or central nervous system, rather than tissue damage, which is referred to as a neuropathic pain.
As therapeutic drugs for these pains, a wide variety of drugs have already been known, which are largely divided with respect to the aspects of action mechanism into opioid analgesics which contain narcotic analgesics such as morphine, codeine, opium alkaloids, buprenorphine, pentazocine, and the like; and antipyretic analgesics (non-narcotic analgesics) such as aspirin, indomethacin, acetaminophen, and the like. While the former provides a strong analgesic effect by acting on the opioid receptor in the central nervous system, its use is limited because it causes severe side effects and dependency. While the latter acts on peripheral tissues to bring about an anti-inflammatory and analgesic effect, the level of the action is low and various side effects may occur. Furthermore, a therapeutic drug effective for a neuropathic pain associated with diabetic neuropathy, trigeminal neuropathy, herpes zoster, and the like has not been found yet, and the development of a pharmaceutical agent effective for a broad range of pains, including these pains, has been desired.
In recent years, during the course of studies relating to the algetic mechanism, a receptor of capsaicin (pungent component of red pepper), known to be an algetic substance, was cloned and named as a vanilloid receptor (hereinafter to be referred to as “VR1”) (see, Nature, vol. 389, p. 816 (1997)).
Since VR1 present in the capsaicin-sensitive sensory nerve is activated not only by a capsaicin-like substance but also by heat, acid (H+), and the like, VR1 is considered to be involved in pain and inflammation associated with various pathologies.
To be specific, when VR1 is activated by the stimuli of capsaicin and the like, the cation channel opens, the membrane is depolarized and neuropeptide is released, which in turn evokes pain and inflammation. Therefore, a substance that antagonizes the activation of VR1 is potentially a superior therapeutic drug for pain and inflammation. In fact, capsazepine, known to be a VR1 receptor antagonist, has been reported to show a remarkable analgesic effect in animal models (see, Life Science, vol. 69, p. 2911 (2001)).
On the other hand, the VR1 agonist capsaicin is also considered to develop intense stimuli (pain) and then induce an analgesic effect or anti-inflammatory effect. It is postulated that capsaicin binds to a receptor to continuously open the VR1 cation channel, which in turn makes the sensory nerve unresponsive to stimuli (see, Pharmacol. Rev., vol. 51, p. 159 (1999)). Since capsaicin has been, in fact, effectively used as an analgesic for pain in diseases such as diabetic neuropathy, rheumatoid arthritis, and the like, a compound (VR1 agonist) having a capsaicin-like action mechanism is also expected to be a therapeutic drug for pain and inflammation.
In addition, a report has been documented that patients with not only pain but also inflammatory bowel diseases (Crohn's disease, ulcerative colitis, etc.) show a high expression of VR1, and therefore, a compound having a capsaicin-like action mechanism or an action mechanism that antagonizes responses of capsaicin is expected to be a good therapeutic drug for inflammatory bowel diseases.
As diseases involving the capsaicin-sensitive sensory nerve, pruritus, allergic and nonallergic rhinitis, hyperactive bladder frequent urination, incontinence, apoplexy, irritable bowel syndrome, respiratory diseases (asthma, chronic obstructive pulmonary disease, etc.), dermatitis, gastric ulcer, duodenal ulcer, and the like are known, and an antiobesity action for capsaicin has been reported. Therefore, a compound having a capsaicin-like action mechanism or an action mechanism that antagonizes responses of capsaicin is also useful as a therapeutic drug for these diseases and conditions.
As mentioned above, a compound having a capsaicin-like action mechanism or an action mechanism that antagonizes responses to capsaicin is highly expected to be a therapeutic drug for neuropathic pain, for which existing analgesics are ineffective, such as diabetic neuropathy and the like, as well as pains caused by various diseases such as rheumatoid arthritis and the like, and further, apart from pain, a therapeutic drug for various diseases in which VR1 is involved, such as ulcerative colitis and the like.
As a capsaicin receptor ligand, a compound having the following formula (a) has been described in a literature
wherein A is a single bond, O, S, NRA, CRBRB′, and the like, Z is O or S, R1 and R2 are each H or alkyl, R3 and R4 are each H, halogen, hydroxy, amino, and the like, or adjacent R3 and R4 are bonded to form an aryl ring and the like, and Ar1 and Ar2 are each optionally substituted cycloalkyl and the like (see, WO02/08221).
In addition, as a vanilloid receptor antagonist, a heterocyclic compound having a urea bond (see, WO02/072536, WO02/090326, and WO03/022809), a thiocarbamic acid derivative (see, WO02/16317), a thiourea derivative (see, WO02/16318 and WO02/16319), a trialkylglycine derivative (see, WO02/28885) and a pyridine derivative (see, WO02/076946) have been reported.
Moreover, a cyanophenyl derivative of the formula (b)
wherein ring A is an optionally substituted 4-8-membered saturated heterocycle, Z1 and Z2 are each CH or a nitrogen atom, X is an oxygen atom, C(R2)R3, and the like, R is cyano or a nitro group, and each R1 is H, halogen, cyano, lower halogenoalkyl, and the like has been reported as an androgen antagonist (see, JP-A-2002-88073).
However, none of these compounds has the structural characteristics of the compound of the below-mentioned formula (I).